Transmucosal dosage forms for brain-targeted steroid chemical delivery systems

Abstract

Provided are pharmaceutical compositions of an essentially saturated complex of a steroidal chemical delivery system with cyclodextrin, formulated into a transmucosal dosage form, and methods for their use.

Description

FIELD OF THE INVENTION The invention relates to a cyclodextrin complex of a chemical delivery system for steroids, formulated into a transmucosal dosage form, and to a method for enhancing the transmucosal bioavailability of the chemical delivery system. BACKGROUND OF THE INVENTION A brain-targeted chemical delivery system (CDS) represents a rational drug design approach which exploits sequential metabolism, not only to deliver but also to target drugs to their site of action. A dihydropyridinepyridinium salt-type redox system has been previously proposed and applied to a number of drugs, including steroidal sex hormones such as estradiol and testosterone and anti-inflammatory steroids such as dexamethasone. According to this redox system, a centrally acting drug [D] is coupled to a quaternary carrier [QC]+ through a reactive functional group (such as a hydroxyl function) in the drug; the [D-QC]+ which results is then reduced chemically to the lipoidal dihydro form [D-DHC]. After ...

AI Technical Summary

Benefits of technology

It is now believed that excess cyclodextrin inhibits the absorption of chemical delivery systems for steroidal sex hormones or anti-inflammatory steroids (S-CDS) from a transmucosal dosage form comprising an S-CDS-cyclodextrin complex, and that a transmucosal dosage form of a saturated S-CDS-cyclodextrin complex improves oral and / or transmucosal bioavailability and / or achieves lower interpatient and / or intrapatient variation of the S-CDS and / or maintains acceptably low peripheral steroid levels.

Problems solved by technology

At the same time, the increased lipophilicity makes it practically impossible to formulate aqueous solutions of these derivatives for injection; moreover, even in organic solvents such as DMSO, they have a propensity for precipitating out of solution upon injection, particularly at higher concentrations and especially at the injection site or in the lungs.

Even in the absence of noticeable crystallization, the redox derivatives frequently display not only the desired concentration in the brain but undesired initial high lung concentrations as well.

Further, the dihydropyridine-containing derivatives suffer from stability problems, since even in the dry state they are very sensitive to oxidation as well as to water addition.

In selected instances, complexation results in substantially improved water solubility of the redox systems as well.

However, no specific formulations are disclosed in the patents except in the case of parenteral administration.

Recently, however, the generally accepted notion that treatment of postmenopausal women with estrogen combined with progestin offered protection from coronary heart disease as well as improvement in health-related quality of life has not proved to be correct.

Recent studies have also shown that elevated peripheral exposure to estrogen is generally undesirable in males.

It is thus apparent that E2-CDS cannot realize its full potential until it can be delivered in a way which will still achieve its therapeutic function but will not significantly elevate peripheral exposure to estrogen.

The cost of parenteral administration is much higher due to the requirement that a health care professional administer the drug in the health care provider setting, which also includes all attendant costs associated with such administration.

Oral delivery is, however, not practical for E2-CDS or the other dihydropyridine redox carrier compounds; the dihydrotrigonellinate moiety in E2-CDS, for example, shows instability in gastrointestinal fluid leading to multiple decomposition products starting with water addition and / or oxidation.

Transmucosal delivery, on the other hand, has never been optimized for these drugs.

Further, the art does not suggest how to maximize or enhance the benefits of complexation in terms of bioavailability and interpatient variation when the complex is to be administered as a transmucosal dosage form.

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